The research will document the role of the genotype in the cardiovascular and metabolic responses to aerobic exercise-training and the contribution of inherited factors in the changes brought about by regular exercise for several cardiovascular disease and diabetes risk factors. A consortium of five laboratories from five different institutions in the U.S. and Canada will be involved in carrying out this study. A total of 650 sedentary subjects will be recruited, initially tested, exercise-trained with the same program for 20-weeks, and re-tested. These subjects will come from 130 families with both parents and three biological adult offsprings, 90 Caucasian and 40 African American families. Oxygen uptake, expiratory volume and respiratory exchange ratio, blood pressure, heart rate, blood lactate, glucose, glycerol and free-fatty acids, stroke volume and cardiac output will be measured during exercise before and after training the maximal oxygen uptake will be determined. Plasma lipids, lipoproteins and apoproteins, glucose tolerance and insulin response to a glucose load, plasma sex steroids and glucocorticoids, resting systolic and diastolic blood pressures, and body fat and regional fat distribution will also be assessed. Nutritional intake, level of habitual physical activity and other lifestyle components will be assessed with three day records and questionnaires. Multivariate genetic analyses and complex segregation analyses will be carried out to develop hypotheses concerning the genetic basis of the response to exercise-training. subsequently, association studies with genetic markers will be undertaken using probes for candidate genes pertaining to key regulatory enzymes of the energy-related pathways, hormones and hormone receptors, and apoproteins for the phenotypes exhibiting a major gene effect through segregation analysis and for the high- and low-responders in health related phenotypes. This research should increase our understanding of human variation, the genetics of adaptation to exercise-training and of the concomitant changes in cardiovascular disease and diabetes risk factors.